Authors: Kehinde Adebayo Babatunde, Oluwadamilola Fatimat Babatunde, Adeel Ahmed, Wilmara Salgado‐Pabon, David J Beebe, Sheena C. Kerr
Published: 2025-05-31
Source: Full article
AbstractPersistent neutrophilic inflammation can lead to tissue damage and chronic inflammation, contributing to non‐healing wounds. The resolution phase of neutrophilic inflammation is critical to preventing tissue damage. Animal models have provided insight into resolution of neutrophilic inflammation via efferocytosis and reverse migration (rM); however, species‐specific differences and complexity of innate immune responses make translation to humans challenging. Thus, there is a need for in vitro systems that can elucidate mechanisms of resolution of human neutrophilic inflammation. Here, a human microphysiological system (MPS) is developed to mimic an inflammatory sterile injury (SI) microenvironment to study the role of macrophage‐derived extracellular vesicles (M‐EVs) in the resolution of inflammation via neutrophil rM. The MPS integrates a blood vessel mimic, injury site spheroid, human neutrophils, macrophages, and macrophage‐derived EVs to investigate the role of M‐EVs in neutrophil rM in vitro. The MPS enabled demonstration that EVs derived from macrophage subsets modulate migratory behavior in primary neutrophils differently in specific inflammatory microenvironments. A new mechanism is identified underlying neutrophil rM, where neutrophils exposed to M2‐EV‐derived‐IL‐8 migrate away from the SI site. Overall, the SI MPS system demonstrates a reverse migratory pattern in human primary neutrophils, advancing the study of the resolution of inflammation via M‐EVs.